Declining immune function of older adults Is a hallmarl< of aging and affects the ability of this vulnerable population to resist influenza and respond to vaccination. Rising hospitalization and death rates due to influenza over the last two decades in spite of widespread influenza vaccination programs, call for more effective influenza vaccines in the older population. There have been major advances in vaccine technology but the phases of clinical development are entirely dependent on antibody responses as correlates of protection and measures of vaccine efficacy. This approach to vaccine development lacks a mechanistic understanding of the age-related changes In the development and maintenance of T cell memory in the reponse to influenza and Influenza vaccination. This project provides a translational approach to understanding how mechanisms of decline with aging of influenza-specific T cell memory responses found in mouse models, apply to studies of peripheral blood mononuclear cells (PBMC) from older people. How T cell memory may be generated or restimulated in response to adjuvanted influenza vaccine formulations is of particular interest. Our long-term goal is to understand how aging affects the Immune response to Influenza and how vaccines could be designed to provide better protection in older people. We will conduct studies to translate recent promising findings In mouse models to establish whether tfie insights gained will be applicable to comparable human naive and memory CD4 and CDS T cells. This 5-year proposal will address the following aims: 1) Elucidate defects in the generation of effector and memory functions in aged naive CD4+ T cells and detennine their potential reversibility. 2) Identify age-related changes in the phenotype and function of memory T-cell subsets responding to live influenza virus challenge. 3) Determine how CD4 and CDS T cell responses to influenza vaccination may be enhanced by adjuvants/vaccines in older adults. RELEVANCE (See instmctions): Relevance: While it is well recognized that current split-virus vacciines provide limited protection in older people, strategies that completely rely on antibody titers have failed to develop more effective vaccines. A mechanistic approach to vaccine development and a greater understanding of how to improve aged memory T cell responses to influenza is needed; an adjuvanted vaccine formulation holds the greatest promise for better proetecion in this population.